Novel compounds exhibiting impressive antiviral and/or antiparasitic properties have recently been described (Manfredi et al., J. Med. Chem., 34, 3402-3405, (1991); Bringmann et al., Angew. Chem. Int. Ed. Eng., 32, 1190-1191, (1993); Boyd et al., J. Med. Chem., 37, 1740-7815, (1994); Boyd et al., U.S. Pat. No. 5,455,251; Bringmann et al , Tetrahedron, 50, 7807-7815, (1994); Hallock, et al., J. Org. Chem., 59, 6349-55 in press, (1994); Bringmann, et al., Heterocycles, 39, 503-512 (1994) in press, 1994b; Bringmann et al., Tetrahedron, 20, 9643-9648, (1994b); Fran.cedilla.ois et al., Phytochemistry, 35, 1461-1464, (1994); Fran.cedilla.ois et al., PCT Application PCT/US95/01717; Boyd et al., U.S. Pat. No. 5,409,938; Bringmann et al., U.S. patent application Ser. No. 08/279,291; and Bringmann et al., U.S. patent application Ser. No. 08/279,339). These compounds are members of a general class known as naphthylisoquinoline alkaloids (Bringmann, The Alkaloids, Vol. 29 (Brossi, ed.), Academic Press, New York, 1986, pp. 141-184), and can further be characterized based on their structure as either monomeric alkaloids (or "monomers") or dimeric alkaloids (or "dimers").
Monomeric alkaloids include korupensamines or related monomeric naphthylisoquinoline alkaloids and derivatives thereof, which typically possess a C-8' to C-5 naphthalene/isoquinoline linkage, and non-korupensamines or other monomeric naphthylisoquinoline alkaloids and derivatives thereof, which typically lack a C-8' to C-5 naphthalene/isoquinoline linkage.
Dimeric alkaloids include michellamines, which based on their molecular structure are comprised of two monomeric alkaloids coupled together (e.g., two monomeric or molecular "halves"). Furthermore, a given michellamine may be either "homodimeric" (comprised of two monomeric halves which are the same) or "heterodimeric" (comprised of two monomeric halves which are different).
Dimeric naphthylisoquinoline alkaloids, as exemplified by the michellamines, have highly desirable and eminently useful medicinal properties that for the most part are distinct from the properties of the monomeric naphthylisoquinoline alkaloids which comprise their molecular halves. For example, the michellamines, such as michellamine B (Boyd et al., U.S. Pat. No. 5,455,251; Boyd et al., 1994, supra) are highly effective inhibitors of the replication and resultant destructive effects of the human immunodeficiency virus (HIV) in human immune cells. The range of anti-HIV activity observed for these dimeric alkaloids is exceptionally broad, encompassing both the major viral types, HIV-1 and HIV-2, as well as diverse HIV strains, and can be observed in different host cells (Boyd et al., 1994, supra).
Moreover, the dimeric alkaloids would appear to comprise a novel antiviral drug class in that the mechanism of action of the michellamines is distinct from any mechanism previously described. Specifically, the mechanism involves at least two components: (1) an inhibition of the viral reverse transcriptase, and (2) an inhibition of the cell-cell fusion process (McMahon et al., Antimicrob. Agents Chemother., 35, 484, 488 (1995)). This suggests that the dimeric alkaloids may prove effective not only in the prevention of nascent viral infection, but also in the prevention of the replication and spread of the virus in vivo and in the prevention of syncytia formation which has been observed in vitro and which may mediate the depletion of T4 immune cells which occurs in vivo.
In addition to the medicinally desirable properties of the dimeric alkaloids, they are also quite attractive from a pharmacological and toxicological standpoint. In vivo doses of michellamine B that are non-toxic result in a level of the drug in the blood which is well in excess of its effective antiviral concentration (Supko et al., Anal. Biochem., 216, 52-60, (1994); Supko et al., Antimicrob. Agents Chemother., 9-14 (1995)).
In contrast, the monomeric naphthylisoquinoline alkaloids appear to be devoid of anti-HIV activity. However, the monomeric alkaloids instead have potent antiparasitic properties as exhibited by their activity against strains of malaria-causing organisms. In this respect, it is interesting to speculate that a trace of this antiparasitic activity may be imparted to the alkaloid dimer by its constituent monomeric halves, as a few of the dimeric naphthylisoquinoline alkaloids (e.g., the michellamines) also appear weakly antiparasitic (Boyd et al., U.S. Pat. No. 5,409,938; Fran.cedilla.ois et al., PCT Application PCT/US95/01717; Fran.cedilla.ois et al., 1994, supra).
Unfortunately, attempts by researchers to maximally exploit the potential of the dimeric alkaloids through development of antiviral and antiparasitic therapy and unprecedented uses for the alkaloids have been hindered by the lack of significant access to the dimeric alkaloids. To date, the only known natural source of the dimeric alkaloids is the rare tropical vine Ancistrocladus korupensis of Central Africa (Thomas and Gereau, Novon 3, 494-498 (1993); Boyd et al., 1994, supra; Hallock et al., 1994, supra). The U.S. National Cancer Institute has actively solicited the research community to engage in efforts to discover methods of synthesis of these compounds, as well as synthesis of improved compounds (Anonymous, J. Nat. Prod., 55, 1018-1019, (1992)).
To address the critical need for synthetic access to michellamines and other medically useful known and new dimeric naphthylisoquinoline alkaloids, a recent, previous invention provided a method of preparation of such compounds by the coupling together of two selected synthetic or naturally occurring monomeric naphthylisoquinoline alkaloids (Bringmann et al., U.S. patent application Ser. No. 08/279,339). More specifically, the previous invention provided a method of preparing a naphthylisoquinoline alkaloid dimer comprising the steps of (a) selecting first and second naphthylisoquinoline alkaloid monomers, which are either the same or different, (b) optionally introducing protective group(s) at desired site(s) in the monomers, (c) introducing activation group(s) at the desired coupling site(s) of the monomers if needed for coupling of the monomers, (d) coupling the first and second monomers to form a dimeric naphthylisoquinoline alkaloid, and (e) optionally removing the protective group(s) from the dimeric naphthylisoquinoline alkaloid.
Thus, in the method of the previous invention, the pre-selected or pre-constructed naphthylisoquinoline monomers, each of which already contains a naphthalene-to-isoquinoline linkage, are coupled together to form the central biaryl axis (naphthalene-to-naphthalene) comprising the dimer. For any particular dimeric compound needed or sought by synthesis, however, an alternate method of preparation providing more efficient or otherwise advantageous access to the naphthylisoquinoline alkaloid dimer would be highly desirable and useful. It would be particularly desirable, for example, to have an alternate method which does not require the use of pre-selected or pre-constructed monomeric naphthylisoquinoline monomers, which may not be immediately or efficiently available. An alternate method providing access not only to known dimeric naphthylisoquinoline alkaloids but also to unprecedented new dimeric arylisoquinolines would be even more desirable.
Accordingly, it is an object of the present invention to provide a new method for synthesizing dimeric arylisoquinoline alkaloids. The distinct novelty of the synthetic strategy is the intermolecular biaryl coupling of intact isoquinoline building blocks to the biaryl centerpiece comprising the desired dimeric product. This synthetic strategy bears some similarities to that disclosed in the method of yet another previous invention which incorporates the intermolecular biaryl coupling of an isoquinoline building block with a naphthalene building block to form a monomeric naphthylisoquinoline alkaloid (Bringmann et al., U.S. patent application Ser. No. 08/279,291). This and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.